FIELD OF THE INVENTION
This invention relates to a novel class of peptidyl .alpha.-ketoamides useful for selectively inhibiting serine proteases, selectively inhibiting cysteine proteases, generally inhibiting all serine proteases, and generally inhibiting all cysteine proteases. Serine proteases and cysteine proteases are involved in numerous disease states and inhibitors for these enzymes can be used therapeutically for the treatment of diseases involving serine proteases or cysteine proteases. We have discovered that peptidyl .alpha.-ketoamides can be constructed to inhibit selectively individual serine or cysteine proteases or groups of serine or cysteine proteases. We have found that peptidyl ketoamides which contain hydrophobic aromatic amino acid residues in the P.sub.1 site are potent inhibitors of chymases and chymotrypsin-like enzymes. Ketoamides containing small hydrophobic amino acid residues at the P.sub.1 position are good inhibitors of elastases. Inhibitors of elastases and chymases are useful as anti-inflammatory agents. We have found that peptide ketoamides which contain cationic amino acid residues such as Arg and Lys in the P.sub.1 site are potent inhibitors of trypsin and blood coagulation enzymes. These inhibitors are thus useful as anticoagulants. Ketoamides with aromatic amino acid residues in the P.sub.1 site would be good inhibitors for cysteine proteases such as papain, cathepsin B, and calpain I and II. Thus, they would have utility as anticancer agents. Ketoamides with either aromatic amino acid residues or small hydrophobic alkyl amino acid residues at P.sub.1 are good inhibitors of calpain I and II. Ketoamides with small alkyl amino acid residues such as Leu or Val at P.sub.2 are also good inhibitors of the calpains. We have found that ketoamides which have both a hydrogen bonding group such as hydroxyl or alkoxy and an aromatic group are more effective inhibitors for calpain I, calpain II, cathepsin B and human neutrophil elastase. Ketoamides which contain a heterocylic group also are more potent inhibitors for calpain I, calpain II, cathepsin B and human neutrophil elastase. The ketoamides which are calpain inhibitors would be useful as neuroprotectants and can be used as therapeutics for the treatment of neurodegeneration, stroke, restenosis, and related diseases.